Alpha1-adrenoceptors mediate dihydroxyphenylalanine-induced activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques.
The mechanisms underlying actions of dihydroxyphenylalanine (L-DOPA) in Parkinson's disease remain to be fully elucidated. Noradrenaline formed from L-DOPA may stimulate alpha(1)-adrenoceptors. We assessed the involvement of alpha(1)-adrenoceptors in actions of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques. In each animal, the minimal dose of L-DOPA required to alleviate parkinsonian symptoms was defined (12.5-25 mg/kg p.o.). The effects of coadministration of the alpha(1)-adrenoceptor antagonist prazosin ([4-(4-amino-6,7-dimethoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone) on motor activity, parkinsonism, and dyskinesia were assessed. Antiparkinsonian benefit was accompanied by mild dyskinesia. L-DOPA also elicited hyperactivity, i.e., activity greater than that seen in normal animals. Coadministration of prazosin (0.16-0.63 mg/kg p.o.) with L-DOPA did not significantly affect either its antiparkinsonian actions or dyskinesia. However, prazosin significantly and dose-dependently attenuated L-DOPA-induced activity, reducing it to a level equivalent to that of normal animals. More specifically, during periods of pronounced L-DOPA-induced activity, prazosin attenuated the total and duration of activity by 80 and 76%, respectively. These actions of prazosin were expressed in the absence of sedation. Although activation of alpha(1)-adrenoceptors plays no major role in the antiparkinsonian and dyskinetic effects of L-DOPA per se, it does contribute to the induction of hyperactivity. alpha(1)-Adrenoceptors may be involved in pathological responses to L-DOPA treatment, including the dopamine dysregulation syndrome.
Visanji
N P
NP
Division of Brain Imaging and Behavior, Toronto Western Research Institute, 399 Bathurst St., Toronto, ON, Canada. naomi.visanji@utoronto.ca
Fox
S H
SH
Johnston
T H
TH
Millan
M J
MJ
Brotchie
J M
JM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001545:Benserazide / Q000494:pharmacology; D001930:Brain Injuries / Q000139:chemically induced / Q000503:physiopathology; D004295:Dihydroxyphenylalanine / Q000494:pharmacology*; D005260:Female; D007980:Levodopa / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D011224:Prazosin / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*
D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D001545:Benserazide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011224:Prazosin